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RET, set, go

Just 15 months after Ret proto-oncogene fusions were first identified in 1%-2% of non-small cell lung cancer cases, early data from a Phase II trial of Exelixis Inc.'s Cometriq cabozantinib suggest that blocking the target could be effective in this patient population.1 At least four additional investigator-initiated trials are seeking to test marketed Ret proto-oncogene inhibitors in fusion-positive lung cancer.

In addition, at least seven clinical trials are testing compounds that inhibit other recently identified oncogenic drivers of lung cancer, including amplifications or mutations in fibroblast growth factor receptors (FGFRs) and mutations in discoidin domain receptor tyrosine kinase 2 (DDR2 (see "Selected new targeted therapies in lung cancer" and Box 1, "Squamous smorgasbord").

The rapid move to the clinic validates the prediction made by clinicians and industry researchers that the identification of new oncogenic drivers of lung cancer would spur the development of targeted therapies for new subsets of patients.2-5

In late 2011 and early 2012, four independent teams reported the expression of a KIF5B-RET oncogenic fusion protein in non-small cell lung cancer (NSCLC) patient samples and showed that the protein was necessary and sufficient to drive unchecked cellular proliferation.6-9 This drew immediate comparisons to the 2007 identification of the EML4-ALK oncogenic fusion protein, which drives about 5% of NSCLC cases.10

A key difference is that when EML4-ALK was discovered, there were no marketed anaplastic lymphoma kinase (ALK) inhibitors. Pfizer Inc.'s Xalkori crizotinib, a dual inhibitor of c-Met receptor tyrosine kinase and ALK and their oncogenic variants, entered the clinic in 2006 and was approved in August 2011 to treat ALK fusion-positive lung cancer.4

In contrast, Ret proto-oncogene (RET) kinase is inhibited by multiple marketed nonspecific tyrosine kinase inhibitors, including Cometriq, Nexavar sorafenib, Sutent sunitinib, Caprelsa vandetanib and Iclusig ponatinib.

Cometriq is marketed by Exelixis to treat medullary thyroid cancer (MTC). Nexavar is marketed by Onyx Pharmaceuticals Inc. and Bayer AG to treat liver and renal

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